Interferon induces the synthesis of a large number of gene products. These products play a role in the antiviral and antiproliferative effects of alpha interferon. Two of the induced gene products, 2',5'-oligoadenylate synthetase and the double-stranded inhibitor (DSI) are induced by interferon but require double-stranded RNA to activate them. The DSI plays a major role in inhibiting protein synthesis initiation by phosphorylating the eukaryotic initiation factor 2 (eIF-2) on serine 51 of its alpha subunit. This study combined administration of interferon alpha and Poly ICLC, a form of double-stranded RNA, in order to determine the optimal dose level of interferon for induction of the DSI and the optimal dose of Poly ICLC for activation of the kinase. Three dose levels of interferon were combined with one of four dose levels of Poly ICLC. This study was designed to determine the toxicity of this combination and the maximal tolerated dose. Dose-limiting toxicity was observed with the combination of interferon 10 mu/m2 and Poly ICLC 0.03 mg/m2. Toxicity consisted of prolonged hypotension requiring hospitalization for intravenous fluid administration. Higher doses of Poly ICLC allowed administration of interferon at the 10 mu/m2 dose level without this toxicity. These results suggest that Poly ICLC may be more toxic at lower doses or that higher doses of ICLC may reduce the toxicity of interferon.